*From the Departments of Medicine (Dr. Loredo) and Psychiatry (Dr. Ancoli-Israel), University of California San Diego, San Diego, CA; and the Department of Psychiatry (Dr. Dimsdale), Veterans Affairs San Diego Healthcare System, San Diego, CA.

Abstract

Study objectives: Continuous positive airway pressure
(CPAP) therapy has become the treatment of choice for obstructive sleep
apnea (OSA). However, the efficacy of CPAP therapy has not been
evaluated against a suitable control. We investigated the effectiveness
of CPAP therapy in improving sleep quality in patients with OSA. We
hypothesized that CPAP improves sleep quality.

Design: Patients were
randomized to receive either CPAP or placebo CPAP (CPAP at an
ineffective pressure) for 7 days in a double-blind fashion. Forty-one
patients completed the protocol. Sleep quality variables, arousals,
sleep arterial oxygen saturation (Sao2), and
respiratory disturbance index (RDI) were assessed at baseline, after 1
day of treatment, and after 7 days of treatment. Repeated measures
analysis of variance was used to evaluate the effects of treatment,
time, and the interaction of the two.

Results: As
expected, CPAP lowered RDI and number of arousals, and increased
Sao2 over time (p = 0.001). Contrary to
expectations, both CPAP and placebo CPAP had comparable effects on
sleep quality as assessed by sleep architecture, sleep efficiency,
total sleep time, and wake after sleep onset time.

Conclusions: This study confirms the effectiveness of CPAP
in lowering the number of arousals and the RDI, and in raising
Sao2. However, our data suggest that short-term
CPAP is no different than placebo in improving sleep architecture.
Further evaluation of the effectiveness of CPAP using a suitable
placebo CPAP in prospective randomized studies is
needed

Continuous
positive airway pressure (CPAP) therapy has become the treatment of
choice for the control of obstructive sleep apnea (OSA). CPAP had been
reported to eliminate snoring, abolish apneas and hypopneas, correct
nocturnal oxyhemoglobin desaturation, improve sleep quality, and
improve excessive daytime somnolence.1–5 Multiple studies
also have reported improvements in daytime fatigue, mood, depression,
cognitive function, and hypertension with CPAP
therapy.6–9 However, to our knowledge, no randomized,
true-placebo-controlled CPAP trials have been performed on any of these
outcome measures. Without an appropriate placebo control, it is
difficult to understand what role CPAP therapy plays on the clinical
improvement noted in OSA patients.

To determine the effectiveness of CPAP in improving sleep quality in
patients with OSA, we randomly assigned OSA patients to receive CPAP or
placebo CPAP in a double-blind fashion. We hypothesized that CPAP would
improve sleep architecture, respiratory disturbance index (RDI), number
of arousals, and arterial oxygen saturation
(Sao2).

Materials and Methods

Subjects

All subjects gave informed consent to the protocol, which was
approved by the University of California San Diego Institutional Review
Board. Forty-eight CPAP-naive OSA patients were studied at the
University of California San Diego Clinical Research Center. Subjects
responded to public service advertisements, were referred from
community physicians, or were referred by previous subjects. Subjects
ranged in age from 30 to 65 years, and their weight was between 1.0 and
1.7 times the ideal body weight, as determined from actuarial
tables (Metropolitan Life Insurance Co; New York,
NY).10 Subjects were excluded if they were receiving
medications known to affect sleep or if they had congestive heart
failure, symptomatic obstructive pulmonary, coronary, or cerebral
vascular disease, history of life-threatening arrhythmias,
cardiomyopathy, history of psychosis, narcolepsy, or currently abused
alcohol or drugs.

Experimental Design

Potential OSA subjects were prescreened with an unattended
overnight home sleep study using a sleep recording system (NightWatch;
Healthdyne Technologies; Marietta, GA). If their RDI was ≥ 20,
the subjects then were admitted to the clinical research center at 5
pm for a confirmatory overnight full polysomnography (PSG)
sleep recording. If on a preliminary interpretation of the PSG
recording the RDI was ≥ 20, subjects were considered to have
significant OSA and were admitted into the study.

On the second night of admission, qualifying subjects were randomized
to receive either traditional nasal CPAP or placebo CPAP for 7 days in
a double-blind fashion

PSG was repeated on the third night after admission (after 1 day
of treatment), and patients then were discharged home for 1 week of
continuing CPAP or placebo CPAP home treatment. Research staff were in
frequent contact with patients to answer questions about mask placement
and to encourage compliance with the therapy. All CPAP units (Horizon,
model 7353D; DeVilbiss; Somerset, PA) had a hidden compliance clock,
which allowed the measurement of the amount of time the CPAP units were
switched on.

On the 11th day of the protocol (after 7 days of treatment) the
subjects were readmitted to undergo a fourth sleep study

Sleep Recordings

Sleep was recorded using a polysomnograph (Model 4412P; Nihon
Koden; Irvine, CA) that recorded central and occipital EEG, bilateral
electrooculogram, submental and tibialis anterior electromyogram (EMG),
ECG, nasal/oral airflow using a thermistor, and respiratory effort
using chest and abdominal inductance belts.
Sao2 was monitored using a pulse
oximeter (Biox 3740; Ohmeda: Louisville, CO) and was analyzed using
computer software (Profox; Escondido, CA).11Sleep records
were scored according to the criteria of Rechtshaffen and
Kales.12

Apneas were defined as decrements in airflow of ≥ 90% from baseline
for a period ≥ 10 s. Hypopneas were defined as decrements in airflow
of ≥ 50% but < 90% from baseline for a period ≥ 10 s. The
number of apneas and hypopneas per hour were calculated to obtain RDI.

The definition of an arousal from sleep was based on the criteria
published in the 1992 American Sleep Disorders Association
Report on EEG arousals13 with some modifications. An
arousal was defined as a shift in EEG frequency to alpha or theta for≥
1.5 s but < 15 s whether or not it was associated with a rise in
chin EMG amplitude, a rise in leg EMG activity, or both. Before an
arousal could be scored, the subject had to have been sleeping for a
minimum of 10 s in the same or the contiguous sleep epoch. A
minimum of 10 s of intervening sleep was necessary to score a
second arousal. Shifts in EEG frequency were scored from either or both
of the EEG derivations (occipital or central). The abrupt appearance of
K-complexes was scored as an arousal only if they were accompanied by
an obvious shift in EEG frequency. The total arousal index was
calculated by dividing the number of arousals by the total sleep time
(TST).

CPAP and Placebo CPAP Titration

In the CPAP-treated group, optimal effective nasal CPAP pressure
to minimize sleep apnea was obtained by conventional manual overnight
CPAP titration during monitoring with PSG. After standard PSG hookup,
the patient was fitted with an appropriately sized nasal CPAP mask
(Respironics; Monroeville, PA). After orientation to the function of
nasal CPAP, the patient was allowed to sleep while the CPAP pressure
was maintained at 2 cm H2O. On the appearance of
unequivocal obstructive apneas or hypopneas, the CPAP pressure was
increased in increments of 2 cm H2O until the
respiratory events were abolished or until a CPAP pressure of 8 to 10
cm H2O was reached. Further pressure titration
then was done in increments of 1 cm H2O based on
the presence of apneas, hypopneas, or snoring associated with arousals.
The titration was considered ended when most respiratory events were
controlled with CPAP while the patient was in the supine position and
in the second or third rapid eye movement (REM) sleep period, or until
a pressure of 20 cm H2O had been reached. If the
frequency of respiratory events was not reduced by > 50%, the CPAP
therapy was considered suboptimal and the patient was discharged from
the study.

Placebo-CPAP subjects underwent a mock titration night during which
CPAP pressure was set at 2 cm H2O using a CPAP
mask (Respironics) containing three 1/4-inch drill holes to create a
large air leak. The pressure at the mask varied from 2 cm
H2O at end-expiration to 1.5 cm
H2O during inspiration. During this procedure,
sleep was monitored with standard PSG as in the CPAP titration
protocol, but the pressure was kept at 2 cm H2O.

Statistical Analysis

Only subjects with a confirmed RDI ≥ 20 on overnight PSG were
included in the analysis. Differences between and within the two
treatment groups over time were assessed using repeated-measures
analysis of variance. This analysis allowed us to test for a main
effect of treatment CPAP vs placebo CPAP, time effect (prior to
treatment, after 1 day of treatment, and after 7 days of treatment),
and the interaction of time by treatment. A time effect alone would
imply that CPAP itself had no specific effect on the variable of
interest. A CPAP-by-time interaction would imply that the CPAP-treated
group, in particular, responded to treatment over time with a
significant response. Statistical analyses were performed using a
statistical computer software package (SPSS for Windows 9.0; SPSS Inc;
Chicago, IL).

Results

Table 1
provides the subjects’ characteristics. Of the 48 subjects admitted
for testing, 1 was removed from the analysis due to breach of
randomization due to severe OSA and severe hypoxemia when using placebo
CPAP. A second patient was removed from the analysis due to inability
to sleep with the CPAP equipment. Five subjects were not included in
the analysis because their RDI on overnight PSG was < 20. The final
sample included 41 subjects with an RDI ≥ 20. The subjects were
predominantly (75%) male. The subjects were moderately obese with an
average weight of 136% of ideal body weight using Metropolitan Life
Insurance Company norms.10 There were no differences
between groups in age, BP, and RDI at baseline. Subjects treated with
CPAP had a significantly greater body mass index (BMI; p = 0.024;
Table 1), and lower mean sleep Sao2
at baseline ( p = 0.011; Table 2
). Both patient groups complied equivalently with CPAP or placebo
treatment over the 1-week interval at home (> 5 h per night use for
each group). The two treatment groups did not differ at baseline on
sleep architecture, TST, wake after sleep onset time (WASO), total
arousal index, or sleep efficiency (Table 2).

There was a significant time effect on sleep latency (p = 0.027),
percentage of stage 1 sleep (p < 0.001), percentage of slow-wave
sleep (SWS; p = 0.001), percentage of REM sleep (p = 0.008), and
sleep efficiency (p = 0.031). TST and WASO did not change with time
or treatment. There was no correlation between compliance and the
posttreatment sleep architecture variables. Using BMI as a measure of
covariance did not alter the results.

Discussion

A wide range of beneficial physiologic, psychological, and
cognitive changes in the OSA patient have been attributed to the
effects of treatment with nasal CPAP.6–8 Nasal CPAP was
primarily designed to reverse by means of a pneumatic splint the
experience of a repetitive collapse of the upper airway by the OSA
patient.14–15 Thus, it has been well documented that CPAP
is effective in abolishing the resultant apneas, hypopneas, and
associated hypoxia and sleep fragmentation.4–5 What is not
clear is whether CPAP is able to correct the poor sleep quality that is
found in OSA patients.

Contrary to our expectations, CPAP was not different than placebo CPAP
in improving sleep quality as assessed by sleep architecture, sleep
efficiency, TST, and WASO. The significant time effect noted in sleep
architecture parameters suggests that the benefits noted in both
treatment groups were not specific to a CPAP effect. Also, compliance
was similar between the CPAP and placebo CPAP groups and was not
related to sleep architecture.

Our findings differ from those reported in the literature
regarding the effect of CPAP on sleep quality. Uncontrolled sleep
studies have reported significant reductions in stage 1 sleep and
increases in REM sleep and SWS in OSA patients treated with
CPAP.1–2 Improvement in sleep architecture also has been
reported in OSA patients using both standard CPAP units and auto-CPAP
technology.3 Had we not used a placebo version of CPAP, we
would have concluded that nasal CPAP had a robust effect in improving
SWS and REM sleep and in reducing stage 1 sleep. That conclusion is not
fully supported by our data.

There are two possible confounding factors affecting our
findings1: Laboratory-based sleep studies are known to
have a first-night effect,16–17 in which sleep quality
tends to be worse than usual during the first night due to the
unfamiliar surroundings and equipment. This was suspected in our study,
as noted by the high baseline sleep latencies in a population with
moderate to severe OSA syndrome. Therefore, an acclimatization effect
could have accounted for some of the changes noted in sleep
architecture for both the CPAP- and placebo CPAP-treated
subjects.2 Another possibility is that the small CPAP
pressure (1.5 to 2 cm H2O) used in our placebo
CPAP group was having a partial therapeutic effect, as suggested by a
significant drop in RDI from baseline to day 1. However, CPAP in the
range used in our placebo CPAP is much lower than would be expected to
significantly reduce the RDI. Berry and Block,18showed
that a minimum CPAP of 4 to 6 cm H2O was required
to control the RDI in sleep apnea subjects of comparable weight to
ours. Previous reports have demonstrated that a mean CPAP of 4 cm
H2O (range, 2.0 to 6.0 cm
H2O) is required just to prevent snoring in
nonapneic subjects.19 In contrast, the average CPAP
required to control sleep apnea in our CPAP-treated group was 10 cm
H2O. Also, in a recent abstract publication,
Stradling et al20 noted a significant placebo CPAP effect
on quality of life using CPAP pressures of < 1 cm
H2O.

We found six studies in the literature examining the effects of CPAP on
OSA that employed some form of placebo control. Four of these studies
utilized an oral placebo,6,21–23 and one randomized
patients to receive nasal cannula air as placebo.24 Only
the report by Jenkinson et al20 used a placebo CPAP
set-up that provided ineffective levels of CPAP (< 1 cm
H2O). In our opinion, the literature pertaining
to the effectiveness of nasal CPAP in the treatment of OSA suffers from
a lack of appropriate placebo CPAP control trials. Despite the
confounding effects of the first-night effect acclimatization and the
possible partial treatment by the placebo CPAP set-up, our findings
suggest that CPAP, when compared with a suitable placebo, may not be as
effective as has been reported in improving sleep architecture
abnormalities of the OSA patient.

This study has a number of limitations. We treated patients for only 1
week because we were concerned about exposing OSA patients to
ineffective CPAP pressure for prolonged periods of time. It is possible
that a longer trial of CPAP could have demonstrated a clear advantage
over placebo CPAP in improving sleep architecture. Although the mean
RDI was > 40, indicating moderate to severe OSA, we excluded
individuals with major medical comorbidity and patients with severe
obesity. Perhaps CPAP would have shown a clearer advantage over placebo
CPAP in patients with more severe derangement of sleep architecture. As
it turned out, subjects randomized to CPAP were more obese and had
lower mean nocturnal Sao2, which
could imply that their OSA was more severe.

Our null findings concerning CPAP efficacy could reflect insufficient
sample size. However, we doubt that sample size accounts for our
findings for a number of reasons: First, our sample size was comparable
to or better than many studies of sleep architecture response to CPAP.
Second, the p values (range, 0.125 to 0.85) for the null findings were
far from significant. Third, if in fact we are committing a type II
error that would be corrected by a larger sample size, we estimate that
we would need to study many more subjects to perceive a significant
CPAP by time interaction (sample size, approximately 80 to 330,
depending on the variable in question). Such large sample size
requirements suggest to us that the magnitude of the short-term effect
of CPAP on sleep architecture, if significant, must be small.

Nevertheless, our study confirms the effectiveness of nasal CPAP in
correcting OSA and the associated arousals and hypoxia. However, our
results suggest that CPAP may not be as effective in improving sleep
architecture in the OSA patient during the first 7 days of treatment.
Further evaluation of the effectiveness of CPAP using a suitable
placebo CPAP in prospective randomized studies is needed.

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